Cysteine proteases, such as cathepsins B, H, K, L, S, and O.sub.2, containing a highly reactive cysteine residue with a free thiol group at the active site have been known as playing an important role in certain conditions distinguished by aberrant protein turnover such as: muscular dystrophy (Am. J. Pathol. 1986, 122, 193-198; Am. J. Pathol. 1987, 127, 461-466), myocardial infarction (J. Am. Coll. Cardiol. 1983, 2, 681-688), bone resorption (Biochem. J. 1991, 279, 167-274; J. Biol. Chem. 1996, 271, 2126-2132; and Biochem. Biophys. Acta 1992,1116, 57-66), arthritis (Arthritis Rheumatism 1994, 37, 236-247; and Biochem. Pharmacol. 1992, 44, 1201-1207),cancer, including cancer metastasis (Cancer Metastasis Rev. 1990, 9, 333-352), pulmonary emphysema (Am. Rev. Respir. Dis. 1975, 111, 579-586), septic shock (Immunol. Today 1991, 11, 404-410, Biochemistry 1994, 33, 3934-3940), cerebral ischemia, memory function, Alzheimer and cataract (TIPS 1994, 15, 412-419, Bioorg. Med. Chem. Lett. 1995 4, 387-392, Proc, Natl. Acad. Sci. USA 1991, 88,10998-11002), malaria (J. Med. Chem. 1995, 38, 5031-5037), glomerular basement membrane degradation (Biochem. Bioph. Acta 1989, 990, 246-251), bacterial infection (Nature 1989, 337, 385-386), inflammatory diseases (Protein Science 1995, 4, 3-12), parasitic infections (Annu. Rev. Microbiol. 1993, 47, 821-853; Parasitol. Today 1990, 6, 270-275), and viral infections (Biochem. 1992, 31, 7862-7869).
A variety of cysteine proteinase have been shown to be present in mammalian tissue. The most notable of these proteinase are the lysosomal cathepsins (cathepsin B, H, S, K and L) and the cytoplasmic Ca.sup.2+ dependent enzymes, the calpains. These enzymes are, therefore, excellent targets for the development of specific inhibitors as possible therapeutic agents.
Several types of cysteine proteases inhibitors have been reported, such as peptide aldehydes (Biochim. Biophys. Acta 1991, 107-343), nitriles (Biochim. Biophys. Acta 1990, 1035, 62-70), halomethyl ketones (Anal. Biochem. 1985, 149, 461-465; Acta. Biol. Med. Ger. 1981, 40, 1503-1511; Biochem. Phar. 1992, 44, 1201-1207), diazomethyl ketones (Biochem. J. 1988, 253, 751), acyloxy methyl ketones (J. Med. Chem. 1994, 37, 1833-1840; J. Am. Chem. Soc. 1988,110, 4429-4431), ketomethylsulfonium salt (J. Biol. Chem. 1988, 263, 2768-2772), .alpha.-ketocarbonyl compounds (J. Med. Chem. 1993, 36, 3472-3480; 1994, 37, 2918-2929), vinyl sulfones (J. Med. Chem. 1995, 38, 3193-3196) and epoxysuccinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527). These inhibitors, in general, have a peptidyl affinity group and a group reactive towards the thiol of the cysteine residue in cysteine proteases.
In continuation of our efforts to find low molecular weight cysteine protease inhibitors for therapeutic uses, we have focused our attention at substituted penam and cepham derivatives of which .beta.-lactam ring is succeptible towards acylation of cysteine proteases.